Methods and compositions utilizing quinazolinones

US 6,545,004 B1
Filed: 10/24/2000
Issued: 04/08/2003
Est. Priority Date: 10/27/1999
Status: Expired due to Term

First Claim

Patent Images

1. A compound of a formula:

whereinR₁is benzyl;

R₂is ethyl;

R₂′

is hydrogen;

R₃is p-tolyl;

R₄is 3-(isopropylamino)propyl;

R₅, R₆, and R₈are hydrogen; and

R₇is chloro;

R₁is p-chlorobenzyl;

R₂is ethyl;

R₂′

is hydrogen;

R₃is p-bromophenyl;

R₄is 2-(dimethylamino)ethyl;

R₅, R₆, and R₈are hydrogen; and

R₇is chloro;

R₁is benzyl;

R₂is ethyl;

R₂′

is hydrogen;

R₃is p-tolyl;

R₄is 3-(dimethylamino)propyl;

R₅, R₆, and R₈are hydrogen; and

R₇is chloro;

R₁is benzyl;

R₂is ethyl;

R₂′

is hydrogen;

R₃is p-tolyl;

R₄is 3-aminopropyl;

R₅, R₆, and R₈are hydrogen; and

R₇is chloro;

R₁is m-methoxybenzyl;

R₂is ethyl;

R₂′

is hydrogen;

R₃is p-tolyl;

R₄is 3-aminopropyl;

R₅, R₆, and R₈are hydrogen; and

R₇is chloro;

R₁is benzyl;

R₂is ethyl;

R₂′

is hydrogen;

R₃is p-bromophenyl;

R₄is 3-aminopropyl;

R₅, R₆, and R₈are hydrogen; and

R₇is chloro;

R₁is benzyl;

R₂is isopropyl;

R₂′

is hydrogen;

R₃is p-tolyl;

R₄is 3-aminopropyl;

R₅, R₆, and R₈are hydrogen; and

R₇is chloro;

R₁is benzyl;

R₂is ethyl;

R₂′

is hydrogen;

R₃is p-tolyl;

R₄is azetidin-3-ylmethyl;

R₅, R₆, and R₈are hydrogen; and

R₇is chloro;

R₁is benzyl;

R₂is ethyl;

R₂′

is hydrogen;

R₃is p-tolyl;

R₄is 2-aminoethyl;

R₅, R₆, and R₈are hydrogen; and

R₇is chloro;

R₁is benzyl;

R₂is ethyl;

R₂′

is hydrogen;

R₃is p-bromophenyl;

R₄is 2-aminoethyl;

R₅, R₆, and R₈are hydrogen; and

R₇is chloro;

R₁is benzyl;

R₂is ethyl;

R₂′

is hydrogen;

R₃is p-tolyl;

R₄is 3-aminopropyl;

R₅, R₆, and R₈are hydrogen; and

R₇is chloro;

R₁is benzyl;

R₂is ethyl;

R₂′

is hydrogen;

R₃is p-tolyl;

R₄is 2-(methylamino)ethyl;

R₅, R₆, and R₈are hydrogen; and

R₇is chloro;

R₁is benzyl;

R₂is ethyl;

R₂′

is hydrogen;

R₃is p-bromophenyl;

R₄is 3-(methylamino)propyl;

R₅, R₆, and R₈are hydrogen; and

R₇is chloro;

R₁is benzyl;

R₂is ethyl;

R₂′

is hydrogen;

R₃is p-bromophenyl;

R₄is 2-(methylamino)ethyl;

R₅, R₆, and R₈are hydrogen; and

R₇is chloro;

R₁is benzyl;

R₂is ethyl;

R₂′

is hydrogen;

R₃is p-tolyl;

R₄is azetidin-2-ylmethyl;

R₅, R₆, and R₈are hydrogen; and

R₇is chloro;

R₁is benzyl;

R₂is ethyl;

R₂′

is hydrogen;

R₃is p-bromophenyl;

R₄is 3-aminopropyl;

R₅, R₆, and R₈are hydrogen; and

R₇is chloro;

R₁is benzyl;

R₂is methylsulfinylmethyl;

R₂′

is hydrogen;

R₃is p-toyl;

R₄is 3-aminopropyl;

R₅, R₆, and R₈are hydrogen; and

R₇is chloro;

R₁is benzyl;

R₂is ethyl;

R₂′

is hydrogen;

R₃is p-tolyl;

R₄is piperidin-3-ylmethyl;

R₅, R₆, and R₈are hydrogen; and

R₇is chloro;

R₁is benzyl;

R₂is ethyl;

R₂′

is hydrogen;

R₃is p-tolyl;

R₄is 3-aminopropyl;

R₅, R₆, and R₈are hydrogen; and

R₇is fluoro;

R₁is benzyl;

R₂is ethyl;

R₂′

is hydrogen;

R₃is p-bromophenyl;

R₄is 2-(dimethylamino)ethyl;

R₅, R₆, and R₈are hydrogen; and

R₇is chloro;

R₁is benzyl;

R₂is ethyl;

R₂′

is hydrogen;

R₃is p-tolyl;

R₄is 2-aminoethyl;

R₅, R₆, R₇and R₈are hydrogen;

R₁is benzyl;

R₂is ethyl;

R₂′

is hydrogen;

R₃is p-tolyl;

R₄is piperidin-2-yl;

R₅, R₆, and R₈are hydrogen; and

R₇is chloro;

R₁is benzyl;

R₂is ethyl;

R₂′

is hydrogen;

R₃is p-bromophenyl;

R₄is 4-aminobutyl;

R₅, R₆, and R₈are hydrogen; and

R₇is chloro;

R₁is m-chlorobenzyl;

R₂is ethyl;

R₂′

is hydrogen;

R₃is p-bromophenyl;

R₄is 2-(dimethylamino)ethyl;

R₅, R₆, and R₈are hydrogen; and

R₇is chloro;

R₁is benzyl;

R₂is ethyl;

R₂′

is hydrogen;

R₃is p-bromophenyl;

R₄is 2-(dimethylamino)ethyl;

R₅, R₆, and R₈are hydrogen; and

R₇is chloro;

R₁is benzyl;

R₂is ethyl;

R₂′

is hydrogen;

R₃is p-tolyl;

R₄is 2-(piperidin-1-yl)ethyl;

R₅, R₆, and R₈are hydrogen; and

R₇is chloro;

R₁is benzyl;

R₂is ethyl;

R₂′

is hydrogen;

R₃is p-tolyl;

R₄is 2-(imidazol-3-yl)ethyl;

R₅, R₆, and R₈are hydrogen; and

R₇is chloro;

R₁is benzyl;

R₂is ethyl;

R₂′

is hydrogen;

R₃is p-tolyl;

R₄is pyrrolidin-3-ylmethyl;

R₅, R₆, and R₈are hydrogen; and

R₇is chloro;

R₁is benzyl;

R₂is ethyl;

R₂′

is hydrogen;

R₃is p-bromophenyl;

R₄is 2-(diethylamino)ethyl;

R₅, R₆, and R₈are hydrogen; and

R₇is chloro;

R₁is benzyl;

R₂is ethyl;

R₂′

is hydrogen;

R₃is p-tolyl;

R₄is 2-(dimethylamino)ethyl;

R₅, R₆, and R₈are hydrogen; and

R₇is chloro;

R₁is benzyl;

R₂is ethyl;

R₂′

is hydrogen;

R₃is p-chlorophenyl;

R₄is 2-(dimethylamino)ethyl;

R₅, R₆, and R₈are hydrogen; and

R₇is chloro;

R₁is benzyl;

R₂is ethyl;

R₂′

is hydrogen;

R₃is p-tolyl;

R₄is 4-aminobutyl;

R₅, R₆, and R₈are hydrogen; and

R₇is chloro;

R₁is benzyl;

R₂is ethyl;

R₂′

is hydrogen;

R₃is p-tolyl;

R₄is pyrrolidin-2-ylmethyl;

R₅, R₆, and R₈are hydrogen; and

R₇is chloro;

R₁is benzyl;

R₂is ethyl;

R₂′

is hydrogen;

R₃is p-tolyl;

R₄is 3-(azetidin-1-yl)propyl;

R₅, R₆, and R₈are hydrogen; and

R₇is chloro;

R₁is benzyl;

R₂is ethyl;

R₂′

is hydrogen;

R₃is p-tolyl;

R₄is 2-(pyrrolidin-1-yl)ethyl;

R₅, R₆, and R₈are hydrogen; and

R₇is chloro;

R₁is benzyl;

R₂is ethyl;

R₂′

is hydrogen;

R₃is p-tolyl;

R₄is 3-(pyrrolidin-1-yl)propyl;

R₅, R₆, and R₈are hydrogen; and

R₇is chloro;

R₁is benzyl;

R₂is ethyl;

R₂′

is hydrogen;

R₃is p-bromophenyl;

R₄is 3-(dimethylamino)propyl;

R₅, R₆, and R₈are hydrogen; and

R₇is chloro;

R₁is benzyl;

R₂is propyl;

R₂′

is hydrogen;

R₃is p-bromophenyl;

R₄is 2-(dimethylamino)ethyl;

R₅, R₆, and R₈are hydrogen; and

R₇is chloro;

R₁is benzyl;

R₂is ethyl;

R₂′

is hydrogen;

R₃is p-bromophenyl;

R₄is 2-(pyrrolidin-1-yl)ethyl;

R₅, R₆, and R₈are hydrogen; and

R₇is chloro;

R₁is benzyl;

R₂is ethyl;

R₂′

is hydrogen;

R₃is p-bromophenyl;

R₄is 3-(pyrrolidin-1-yl)propyl;

R₅, R₆, and R₈are hydrogen; and

R₇is chloro;

R₁is benzyl;

R₂is ethyl;

R₂′

is hydrogen;

R₃is p-tolyl;

R₄is piperidin-4-ylmethyl;

R₅, R₆, and R₈are hydrogen; and

R₇is chloro;

R₁is benzyl;

R₂is methylsulfinylethyl;

R₂′

is hydrogen;

R₃is p-tolyl;

R₄is 3-aminopropyl;

R₅, R₆, and R₈are hydrogen; and

R₇is chloro;

R₁is benzyl;

R₂is ethyl;

R₂′

is hydrogen;

R₃is p-tolyl;

R₄is 3-(piperidin-1-yl)propyl;

R₅, R₆, and R₈are hydrogen; and

R₇is chloro;

R₁is benzyl;

R₂is benzyl;

R₂′

is hydrogen;

R₃is p-tolyl;

R₄is 3-aminopropyl;

R₅, R₆, and R₈are hydrogen; and

R₇is chloro;

R₁is benzyl;

R₂is ethyl;

R₂′

is hydrogen;

R₃is p-bromophenyl;

R₄is (N-ethylpyrrolidin-2-yl)methyl;

R₅, R₆, and R₈are hydrogen; and

R₇is chloro;

R₁is benzyl;

R₂is ethyl;

R₂′

is hydrogen;

R₃is p-tolyl;

R₄is 3-piperidinyl;

R₅, R₆, and R₈are hydrogen; and

R₇is chloro;

R₁is benzyl;

R₂is ethyl;

R₂′

is hydrogen;

R₃is p-tolyl;

R₄is 4-piperidinyl;

R₅, R₆, and R₈are hydrogen; and

R₇is chloro;

R₁is p-chlorobenzyl;

R₂is ethyl;

R₂′

is hydrogen;

R₃is p-bromophenyl;

R₄is 2-(dimethylamino)ethyl;

R₅, R₆, and R₈are hydrogen; and

R₇is chloro;

R₁is benzyl;

R₂is ethyl;

R₂′

is hydrogen;

R₃is p-bromophenyl;

R₄is 2,2-dimethyl-3-(dimethylamino)propyl;

R₅, R₆, and R₈are hydrogen; and

R₇is chloro;

R₁is benzyl;

R₂is ethyl;

R₂′

is hydrogen;

R₃is p-bromophenyl;

R₄is 5-aminopentyl;

R₅, R₆, and R₈are hydrogen; and

R₇is chloro;

R₁is benzyl;

R₂is ethyl;

R₂′

is hydrogen;

R₃is p-tolyl;

R₄is 3-(dimethylamino)propyl;

R₅, R₆, and R₈are hydrogen; and

R₇is fluoro;

R₁is benzyl;

R₂is ethyl;

R₂′

is hydrogen;

R₃is p-bromophenyl;

R₄is 3-(2-methylpiperidin-1-yl)propyl;

R₅, R₆, and R₈are hydrogen; and

R₇is chloro;

R₁is benzyl;

R₂is ethyl;

R₂′

is hydrogen;

R₃is p-tolyl;

R₄is 2-(dimethylamino)ethyl;

R₅, R₆, and R₈are hydrogen; and

R₇is fluoro;

R₁is benzyl;

R₂is ethyl;

R₂′

is hydrogen;

R₃is p-bromophenyl;

R₄is 2-(N-methylpyrrolidin-2-yl)ethyl;

R₅, R₆, and R₈are hydrogen; and

R₇is chloro;

R₁is benzyl;

R₂is ethyl;

R₂′

is hydrogen;

R₃is p-trifluoromethylphenyl;

R₄is 3-(dimethylamino)propyl;

R₅, R₆, and R₈are hydrogen; and

R₇is chloro;

R₁is benzyl;

R₂is ethyl;

R₂′

is hydrogen;

R₃is p-bromophenyl;

R₄is 3-(diethylamino)propyl;

R₅, R₆, and R₈are hydrogen; and

R₇is chloro;

R₁is benzyl;

R₂is ethyl;

R₂′

is hydrogen;

R₃is p-bromophenyl;

R₄is 3-(N-methylpiperazin-1-yl)propyl;

R₅, R₆, and R₈are hydrogen; and

R₇is chloro;

R₁is benzyl;

R₂is 4-(CBZ)aminobutyl;

R₂′

is hydrogen;

R₃is p-tolyl;

R₄is 3-aminopropyl;

R₅, R₆, and R₈are hydrogen; and

R₇is chloro;

R₁is benzyl;

R₂is ethyl;

R₂′

is hydrogen;

R₃is p-bromophenyl;

R₄is aminoethoxyethyl;

R₅, R₆, and R₈are hydrogen; and

R₇is chloro;

R₁is benzyl;

R₂is ethyl;

R₂′

is hydrogen;

R₃is 2-naphthyl;

R₄is 2-(dimethylamino)ethyl;

R₅, R₆, and R₈are hydrogen; and

R₇is chloro R₁is benzyl;

R₂is cyclohexylmethyl;

R₂′

is hydrogen;

R₃is p-tolyl;

R₄is 3-aminopropyl;

R₅, R₆, and R₈are hydrogen; and

R₇is chloro;

R₁is benzyl;

R₂is ethyl;

R₂′

is hydrogen;

R₃is p-bromophenyl;

R₄is 2-(piperidin-1-yl)ethyl;

R₅, R₆, and R₈are hydrogen; and

R₇is chloro;

R₁is benzyl;

R₂is ethyl;

R₂′

is hydrogen;

R₃is p-tolyl;

R₄is 3-hydroxypropyl;

R₅, R₆, and R₈are hydrogen; and

R₇is chloro;

R₁is benzyl;

R₂is ethyl;

R₂′

is hydrogen;

R₃is p-fluorophenyl;

R₄is 2-(dimethylamino)ethyl;

R₅, R₆, and R₈are hydrogen; and

R₇is chloro;

R₁is benzyl;

R₂is ethyl;

R₂′

is hydrogen;

R₃is p-bromophenyl;

R₄is 6-aminohexyl;

R₅, R₆, and R₈are hydrogen; and

R₇is chloro;

R₁is benzyl;

R₂is ethyl;

R₂′

is hydrogen;

R₃is p-tolyl;

R₄is 2-(dimethylamino)ethyl;

R₅, R₇, and R₈are hydrogen; and

R₆is chloro;

R₁is benzyl;

R₂is ethyl;

R₂′

is hydrogen;

R₃is p-bromophenyl;

R₄is 2-(dimethylamino)ethyl;

R₅, R₆, and R₈are hydrogen; and

R₇is fluoro;

R₁is benzyl;

R₂is methyl;

R₂′

is hydrogen;

R₃is p-bromophenyl;

R₄is 2-aminoethyl;

R₅, R₆, R₇and R₈are hydrogen;

R₁is benzyl;

R₂is ethyl;

R₂′

is hydrogen;

R₃is p-tolyl;

R₄is 2-(dimethylamino)ethyl;

R₅, R₆, and R₇are hydrogen; and

R₈is chloro;

R₁is benzyl;

R₂is ethyl;

R₂′

is hydrogen;

R₃is p-bromophenyl;

R₄is 2-(dimethylamino)ethyl;

R₆, R₇, and R₈are hydrogen; and

R₅is chloro;

R₁is benzyl;

R₂is aminobutyl;

R₂′

is hydrogen;

R₃is p-tolyl;

R₄is 3-aminopropyl;

R₅, R₆, and R₈are hydrogen; and

R₇is chloro;

R₁is benzyl;

R₂is ethyl;

R₂′

is hydrogen;

R₃is p-tolyl;

R₄is 2-(dimethylamino)ethyl;

R₅and R₈are hydrogen; and

R₆and R₇are fluoro;

R₁is m-tolyl;

R₂is ethyl;

R₂′

is hydrogen;

R₃is p-bromophenyl;

R₄is 2-(dimethylamino)ethyl;

R₅, R₆, and R₈are hydrogen; and

R₇is chloro;

R₁is benzyl;

R₂is ethyl;

R₂′

is hydrogen;

R₃is p-bromophenyl;

R₄is 2-(dimethylamino)ethyl;

R₅and R₈are hydrogen; and

R₆and R₇are fluoro;

or R₁is benzyl;

R₂is ethyl;

R₂′

is hydrogen;

R₃is p-bromophenyl;

R₄is 2-carboxyethyl;

R₅, R₆, and R₈are hydrogen; and

R₇is chloro, or a pharmaceutically acceptable salt of any of the foregoing compounds.

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Abstract

Quinazolinones of formulae 1a, 1b, 1c and 1d are disclosed. They are useful for treating cellular proliferative diseases and disorders associated with KSP kinesin activity. embedded image

Citations

22 Claims

1. A compound of a formula:
- whereinR₁is benzyl;
  
  R₂is ethyl;
  
  R₂′
  
  is hydrogen;
  
  R₃is p-tolyl;
  
  R₄is 3-(isopropylamino)propyl;
  
  R₅, R₆, and R₈are hydrogen; and
  
  R₇is chloro;
  
  R₁is p-chlorobenzyl;
  
  R₂is ethyl;
  
  R₂′
  
  is hydrogen;
  
  R₃is p-bromophenyl;
  
  R₄is 2-(dimethylamino)ethyl;
  
  R₅, R₆, and R₈are hydrogen; and
  
  R₇is chloro;
  
  R₁is benzyl;
  
  R₂is ethyl;
  
  R₂′
  
  is hydrogen;
  
  R₃is p-tolyl;
  
  R₄is 3-(dimethylamino)propyl;
  
  R₅, R₆, and R₈are hydrogen; and
  
  R₇is chloro;
  
  R₁is benzyl;
  
  R₂is ethyl;
  
  R₂′
  
  is hydrogen;
  
  R₃is p-tolyl;
  
  R₄is 3-aminopropyl;
  
  R₅, R₆, and R₈are hydrogen; and
  
  R₇is chloro;
  
  R₁is m-methoxybenzyl;
  
  R₂is ethyl;
  
  R₂′
  
  is hydrogen;
  
  R₃is p-tolyl;
  
  R₄is 3-aminopropyl;
  
  R₅, R₆, and R₈are hydrogen; and
  
  R₇is chloro;
  
  R₁is benzyl;
  
  R₂is ethyl;
  
  R₂′
  
  is hydrogen;
  
  R₃is p-bromophenyl;
  
  R₄is 3-aminopropyl;
  
  R₅, R₆, and R₈are hydrogen; and
  
  R₇is chloro;
  
  R₁is benzyl;
  
  R₂is isopropyl;
  
  R₂′
  
  is hydrogen;
  
  R₃is p-tolyl;
  
  R₄is 3-aminopropyl;
  
  R₅, R₆, and R₈are hydrogen; and
  
  R₇is chloro;
  
  R₁is benzyl;
  
  R₂is ethyl;
  
  R₂′
  
  is hydrogen;
  
  R₃is p-tolyl;
  
  R₄is azetidin-3-ylmethyl;
  
  R₅, R₆, and R₈are hydrogen; and
  
  R₇is chloro;
  
  R₁is benzyl;
  
  R₂is ethyl;
  
  R₂′
  
  is hydrogen;
  
  R₃is p-tolyl;
  
  R₄is 2-aminoethyl;
  
  R₅, R₆, and R₈are hydrogen; and
  
  R₇is chloro;
  
  R₁is benzyl;
  
  R₂is ethyl;
  
  R₂′
  
  is hydrogen;
  
  R₃is p-bromophenyl;
  
  R₄is 2-aminoethyl;
  
  R₅, R₆, and R₈are hydrogen; and
  
  R₇is chloro;
  
  R₁is benzyl;
  
  R₂is ethyl;
  
  R₂′
  
  is hydrogen;
  
  R₃is p-tolyl;
  
  R₄is 3-aminopropyl;
  
  R₅, R₆, and R₈are hydrogen; and
  
  R₇is chloro;
  
  R₁is benzyl;
  
  R₂is ethyl;
  
  R₂′
  
  is hydrogen;
  
  R₃is p-tolyl;
  
  R₄is 2-(methylamino)ethyl;
  
  R₅, R₆, and R₈are hydrogen; and
  
  R₇is chloro;
  
  R₁is benzyl;
  
  R₂is ethyl;
  
  R₂′
  
  is hydrogen;
  
  R₃is p-bromophenyl;
  
  R₄is 3-(methylamino)propyl;
  
  R₅, R₆, and R₈are hydrogen; and
  
  R₇is chloro;
  
  R₁is benzyl;
  
  R₂is ethyl;
  
  R₂′
  
  is hydrogen;
  
  R₃is p-bromophenyl;
  
  R₄is 2-(methylamino)ethyl;
  
  R₅, R₆, and R₈are hydrogen; and
  
  R₇is chloro;
  
  R₁is benzyl;
  
  R₂is ethyl;
  
  R₂′
  
  is hydrogen;
  
  R₃is p-tolyl;
  
  R₄is azetidin-2-ylmethyl;
  
  R₅, R₆, and R₈are hydrogen; and
  
  R₇is chloro;
  
  R₁is benzyl;
  
  R₂is ethyl;
  
  R₂′
  
  is hydrogen;
  
  R₃is p-bromophenyl;
  
  R₄is 3-aminopropyl;
  
  R₅, R₆, and R₈are hydrogen; and
  
  R₇is chloro;
  
  R₁is benzyl;
  
  R₂is methylsulfinylmethyl;
  
  R₂′
  
  is hydrogen;
  
  R₃is p-toyl;
  
  R₄is 3-aminopropyl;
  
  R₅, R₆, and R₈are hydrogen; and
  
  R₇is chloro;
  
  R₁is benzyl;
  
  R₂is ethyl;
  
  R₂′
  
  is hydrogen;
  
  R₃is p-tolyl;
  
  R₄is piperidin-3-ylmethyl;
  
  R₅, R₆, and R₈are hydrogen; and
  
  R₇is chloro;
  
  R₁is benzyl;
  
  R₂is ethyl;
  
  R₂′
  
  is hydrogen;
  
  R₃is p-tolyl;
  
  R₄is 3-aminopropyl;
  
  R₅, R₆, and R₈are hydrogen; and
  
  R₇is fluoro;
  
  R₁is benzyl;
  
  R₂is ethyl;
  
  R₂′
  
  is hydrogen;
  
  R₃is p-bromophenyl;
  
  R₄is 2-(dimethylamino)ethyl;
  
  R₅, R₆, and R₈are hydrogen; and
  
  R₇is chloro;
  
  R₁is benzyl;
  
  R₂is ethyl;
  
  R₂′
  
  is hydrogen;
  
  R₃is p-tolyl;
  
  R₄is 2-aminoethyl;
  
  R₅, R₆, R₇and R₈are hydrogen;
  
  R₁is benzyl;
  
  R₂is ethyl;
  
  R₂′
  
  is hydrogen;
  
  R₃is p-tolyl;
  
  R₄is piperidin-2-yl;
  
  R₅, R₆, and R₈are hydrogen; and
  
  R₇is chloro;
  
  R₁is benzyl;
  
  R₂is ethyl;
  
  R₂′
  
  is hydrogen;
  
  R₃is p-bromophenyl;
  
  R₄is 4-aminobutyl;
  
  R₅, R₆, and R₈are hydrogen; and
  
  R₇is chloro;
  
  R₁is m-chlorobenzyl;
  
  R₂is ethyl;
  
  R₂′
  
  is hydrogen;
  
  R₃is p-bromophenyl;
  
  R₄is 2-(dimethylamino)ethyl;
  
  R₅, R₆, and R₈are hydrogen; and
  
  R₇is chloro;
  
  R₁is benzyl;
  
  R₂is ethyl;
  
  R₂′
  
  is hydrogen;
  
  R₃is p-bromophenyl;
  
  R₄is 2-(dimethylamino)ethyl;
  
  R₅, R₆, and R₈are hydrogen; and
  
  R₇is chloro;
  
  R₁is benzyl;
  
  R₂is ethyl;
  
  R₂′
  
  is hydrogen;
  
  R₃is p-tolyl;
  
  R₄is 2-(piperidin-1-yl)ethyl;
  
  R₅, R₆, and R₈are hydrogen; and
  
  R₇is chloro;
  
  R₁is benzyl;
  
  R₂is ethyl;
  
  R₂′
  
  is hydrogen;
  
  R₃is p-tolyl;
  
  R₄is 2-(imidazol-3-yl)ethyl;
  
  R₅, R₆, and R₈are hydrogen; and
  
  R₇is chloro;
  
  R₁is benzyl;
  
  R₂is ethyl;
  
  R₂′
  
  is hydrogen;
  
  R₃is p-tolyl;
  
  R₄is pyrrolidin-3-ylmethyl;
  
  R₅, R₆, and R₈are hydrogen; and
  
  R₇is chloro;
  
  R₁is benzyl;
  
  R₂is ethyl;
  
  R₂′
  
  is hydrogen;
  
  R₃is p-bromophenyl;
  
  R₄is 2-(diethylamino)ethyl;
  
  R₅, R₆, and R₈are hydrogen; and
  
  R₇is chloro;
  
  R₁is benzyl;
  
  R₂is ethyl;
  
  R₂′
  
  is hydrogen;
  
  R₃is p-tolyl;
  
  R₄is 2-(dimethylamino)ethyl;
  
  R₅, R₆, and R₈are hydrogen; and
  
  R₇is chloro;
  
  R₁is benzyl;
  
  R₂is ethyl;
  
  R₂′
  
  is hydrogen;
  
  R₃is p-chlorophenyl;
  
  R₄is 2-(dimethylamino)ethyl;
  
  R₅, R₆, and R₈are hydrogen; and
  
  R₇is chloro;
  
  R₁is benzyl;
  
  R₂is ethyl;
  
  R₂′
  
  is hydrogen;
  
  R₃is p-tolyl;
  
  R₄is 4-aminobutyl;
  
  R₅, R₆, and R₈are hydrogen; and
  
  R₇is chloro;
  
  R₁is benzyl;
  
  R₂is ethyl;
  
  R₂′
  
  is hydrogen;
  
  R₃is p-tolyl;
  
  R₄is pyrrolidin-2-ylmethyl;
  
  R₅, R₆, and R₈are hydrogen; and
  
  R₇is chloro;
  
  R₁is benzyl;
  
  R₂is ethyl;
  
  R₂′
  
  is hydrogen;
  
  R₃is p-tolyl;
  
  R₄is 3-(azetidin-1-yl)propyl;
  
  R₅, R₆, and R₈are hydrogen; and
  
  R₇is chloro;
  
  R₁is benzyl;
  
  R₂is ethyl;
  
  R₂′
  
  is hydrogen;
  
  R₃is p-tolyl;
  
  R₄is 2-(pyrrolidin-1-yl)ethyl;
  
  R₅, R₆, and R₈are hydrogen; and
  
  R₇is chloro;
  
  R₁is benzyl;
  
  R₂is ethyl;
  
  R₂′
  
  is hydrogen;
  
  R₃is p-tolyl;
  
  R₄is 3-(pyrrolidin-1-yl)propyl;
  
  R₅, R₆, and R₈are hydrogen; and
  
  R₇is chloro;
  
  R₁is benzyl;
  
  R₂is ethyl;
  
  R₂′
  
  is hydrogen;
  
  R₃is p-bromophenyl;
  
  R₄is 3-(dimethylamino)propyl;
  
  R₅, R₆, and R₈are hydrogen; and
  
  R₇is chloro;
  
  R₁is benzyl;
  
  R₂is propyl;
  
  R₂′
  
  is hydrogen;
  
  R₃is p-bromophenyl;
  
  R₄is 2-(dimethylamino)ethyl;
  
  R₅, R₆, and R₈are hydrogen; and
  
  R₇is chloro;
  
  R₁is benzyl;
  
  R₂is ethyl;
  
  R₂′
  
  is hydrogen;
  
  R₃is p-bromophenyl;
  
  R₄is 2-(pyrrolidin-1-yl)ethyl;
  
  R₅, R₆, and R₈are hydrogen; and
  
  R₇is chloro;
  
  R₁is benzyl;
  
  R₂is ethyl;
  
  R₂′
  
  is hydrogen;
  
  R₃is p-bromophenyl;
  
  R₄is 3-(pyrrolidin-1-yl)propyl;
  
  R₅, R₆, and R₈are hydrogen; and
  
  R₇is chloro;
  
  R₁is benzyl;
  
  R₂is ethyl;
  
  R₂′
  
  is hydrogen;
  
  R₃is p-tolyl;
  
  R₄is piperidin-4-ylmethyl;
  
  R₅, R₆, and R₈are hydrogen; and
  
  R₇is chloro;
  
  R₁is benzyl;
  
  R₂is methylsulfinylethyl;
  
  R₂′
  
  is hydrogen;
  
  R₃is p-tolyl;
  
  R₄is 3-aminopropyl;
  
  R₅, R₆, and R₈are hydrogen; and
  
  R₇is chloro;
  
  R₁is benzyl;
  
  R₂is ethyl;
  
  R₂′
  
  is hydrogen;
  
  R₃is p-tolyl;
  
  R₄is 3-(piperidin-1-yl)propyl;
  
  R₅, R₆, and R₈are hydrogen; and
  
  R₇is chloro;
  
  R₁is benzyl;
  
  R₂is benzyl;
  
  R₂′
  
  is hydrogen;
  
  R₃is p-tolyl;
  
  R₄is 3-aminopropyl;
  
  R₅, R₆, and R₈are hydrogen; and
  
  R₇is chloro;
  
  R₁is benzyl;
  
  R₂is ethyl;
  
  R₂′
  
  is hydrogen;
  
  R₃is p-bromophenyl;
  
  R₄is (N-ethylpyrrolidin-2-yl)methyl;
  
  R₅, R₆, and R₈are hydrogen; and
  
  R₇is chloro;
  
  R₁is benzyl;
  
  R₂is ethyl;
  
  R₂′
  
  is hydrogen;
  
  R₃is p-tolyl;
  
  R₄is 3-piperidinyl;
  
  R₅, R₆, and R₈are hydrogen; and
  
  R₇is chloro;
  
  R₁is benzyl;
  
  R₂is ethyl;
  
  R₂′
  
  is hydrogen;
  
  R₃is p-tolyl;
  
  R₄is 4-piperidinyl;
  
  R₅, R₆, and R₈are hydrogen; and
  
  R₇is chloro;
  
  R₁is p-chlorobenzyl;
  
  R₂is ethyl;
  
  R₂′
  
  is hydrogen;
  
  R₃is p-bromophenyl;
  
  R₄is 2-(dimethylamino)ethyl;
  
  R₅, R₆, and R₈are hydrogen; and
  
  R₇is chloro;
  
  R₁is benzyl;
  
  R₂is ethyl;
  
  R₂′
  
  is hydrogen;
  
  R₃is p-bromophenyl;
  
  R₄is 2,2-dimethyl-3-(dimethylamino)propyl;
  
  R₅, R₆, and R₈are hydrogen; and
  
  R₇is chloro;
  
  R₁is benzyl;
  
  R₂is ethyl;
  
  R₂′
  
  is hydrogen;
  
  R₃is p-bromophenyl;
  
  R₄is 5-aminopentyl;
  
  R₅, R₆, and R₈are hydrogen; and
  
  R₇is chloro;
  
  R₁is benzyl;
  
  R₂is ethyl;
  
  R₂′
  
  is hydrogen;
  
  R₃is p-tolyl;
  
  R₄is 3-(dimethylamino)propyl;
  
  R₅, R₆, and R₈are hydrogen; and
  
  R₇is fluoro;
  
  R₁is benzyl;
  
  R₂is ethyl;
  
  R₂′
  
  is hydrogen;
  
  R₃is p-bromophenyl;
  
  R₄is 3-(2-methylpiperidin-1-yl)propyl;
  
  R₅, R₆, and R₈are hydrogen; and
  
  R₇is chloro;
  
  R₁is benzyl;
  
  R₂is ethyl;
  
  R₂′
  
  is hydrogen;
  
  R₃is p-tolyl;
  
  R₄is 2-(dimethylamino)ethyl;
  
  R₅, R₆, and R₈are hydrogen; and
  
  R₇is fluoro;
  
  R₁is benzyl;
  
  R₂is ethyl;
  
  R₂′
  
  is hydrogen;
  
  R₃is p-bromophenyl;
  
  R₄is 2-(N-methylpyrrolidin-2-yl)ethyl;
  
  R₅, R₆, and R₈are hydrogen; and
  
  R₇is chloro;
  
  R₁is benzyl;
  
  R₂is ethyl;
  
  R₂′
  
  is hydrogen;
  
  R₃is p-trifluoromethylphenyl;
  
  R₄is 3-(dimethylamino)propyl;
  
  R₅, R₆, and R₈are hydrogen; and
  
  R₇is chloro;
  
  R₁is benzyl;
  
  R₂is ethyl;
  
  R₂′
  
  is hydrogen;
  
  R₃is p-bromophenyl;
  
  R₄is 3-(diethylamino)propyl;
  
  R₅, R₆, and R₈are hydrogen; and
  
  R₇is chloro;
  
  R₁is benzyl;
  
  R₂is ethyl;
  
  R₂′
  
  is hydrogen;
  
  R₃is p-bromophenyl;
  
  R₄is 3-(N-methylpiperazin-1-yl)propyl;
  
  R₅, R₆, and R₈are hydrogen; and
  
  R₇is chloro;
  
  R₁is benzyl;
  
  R₂is 4-(CBZ)aminobutyl;
  
  R₂′
  
  is hydrogen;
  
  R₃is p-tolyl;
  
  R₄is 3-aminopropyl;
  
  R₅, R₆, and R₈are hydrogen; and
  
  R₇is chloro;
  
  R₁is benzyl;
  
  R₂is ethyl;
  
  R₂′
  
  is hydrogen;
  
  R₃is p-bromophenyl;
  
  R₄is aminoethoxyethyl;
  
  R₅, R₆, and R₈are hydrogen; and
  
  R₇is chloro;
  
  R₁is benzyl;
  
  R₂is ethyl;
  
  R₂′
  
  is hydrogen;
  
  R₃is 2-naphthyl;
  
  R₄is 2-(dimethylamino)ethyl;
  
  R₅, R₆, and R₈are hydrogen; and
  
  R₇is chloro R₁is benzyl;
  
  R₂is cyclohexylmethyl;
  
  R₂′
  
  is hydrogen;
  
  R₃is p-tolyl;
  
  R₄is 3-aminopropyl;
  
  R₅, R₆, and R₈are hydrogen; and
  
  R₇is chloro;
  
  R₁is benzyl;
  
  R₂is ethyl;
  
  R₂′
  
  is hydrogen;
  
  R₃is p-bromophenyl;
  
  R₄is 2-(piperidin-1-yl)ethyl;
  
  R₅, R₆, and R₈are hydrogen; and
  
  R₇is chloro;
  
  R₁is benzyl;
  
  R₂is ethyl;
  
  R₂′
  
  is hydrogen;
  
  R₃is p-tolyl;
  
  R₄is 3-hydroxypropyl;
  
  R₅, R₆, and R₈are hydrogen; and
  
  R₇is chloro;
  
  R₁is benzyl;
  
  R₂is ethyl;
  
  R₂′
  
  is hydrogen;
  
  R₃is p-fluorophenyl;
  
  R₄is 2-(dimethylamino)ethyl;
  
  R₅, R₆, and R₈are hydrogen; and
  
  R₇is chloro;
  
  R₁is benzyl;
  
  R₂is ethyl;
  
  R₂′
  
  is hydrogen;
  
  R₃is p-bromophenyl;
  
  R₄is 6-aminohexyl;
  
  R₅, R₆, and R₈are hydrogen; and
  
  R₇is chloro;
  
  R₁is benzyl;
  
  R₂is ethyl;
  
  R₂′
  
  is hydrogen;
  
  R₃is p-tolyl;
  
  R₄is 2-(dimethylamino)ethyl;
  
  R₅, R₇, and R₈are hydrogen; and
  
  R₆is chloro;
  
  R₁is benzyl;
  
  R₂is ethyl;
  
  R₂′
  
  is hydrogen;
  
  R₃is p-bromophenyl;
  
  R₄is 2-(dimethylamino)ethyl;
  
  R₅, R₆, and R₈are hydrogen; and
  
  R₇is fluoro;
  
  R₁is benzyl;
  
  R₂is methyl;
  
  R₂′
  
  is hydrogen;
  
  R₃is p-bromophenyl;
  
  R₄is 2-aminoethyl;
  
  R₅, R₆, R₇and R₈are hydrogen;
  
  R₁is benzyl;
  
  R₂is ethyl;
  
  R₂′
  
  is hydrogen;
  
  R₃is p-tolyl;
  
  R₄is 2-(dimethylamino)ethyl;
  
  R₅, R₆, and R₇are hydrogen; and
  
  R₈is chloro;
  
  R₁is benzyl;
  
  R₂is ethyl;
  
  R₂′
  
  is hydrogen;
  
  R₃is p-bromophenyl;
  
  R₄is 2-(dimethylamino)ethyl;
  
  R₆, R₇, and R₈are hydrogen; and
  
  R₅is chloro;
  
  R₁is benzyl;
  
  R₂is aminobutyl;
  
  R₂′
  
  is hydrogen;
  
  R₃is p-tolyl;
  
  R₄is 3-aminopropyl;
  
  R₅, R₆, and R₈are hydrogen; and
  
  R₇is chloro;
  
  R₁is benzyl;
  
  R₂is ethyl;
  
  R₂′
  
  is hydrogen;
  
  R₃is p-tolyl;
  
  R₄is 2-(dimethylamino)ethyl;
  
  R₅and R₈are hydrogen; and
  
  R₆and R₇are fluoro;
  
  R₁is m-tolyl;
  
  R₂is ethyl;
  
  R₂′
  
  is hydrogen;
  
  R₃is p-bromophenyl;
  
  R₄is 2-(dimethylamino)ethyl;
  
  R₅, R₆, and R₈are hydrogen; and
  
  R₇is chloro;
  
  R₁is benzyl;
  
  R₂is ethyl;
  
  R₂′
  
  is hydrogen;
  
  R₃is p-bromophenyl;
  
  R₄is 2-(dimethylamino)ethyl;
  
  R₅and R₈are hydrogen; and
  
  R₆and R₇are fluoro;
  
  or R₁is benzyl;
  
  R₂is ethyl;
  
  R₂′
  
  is hydrogen;
  
  R₃is p-bromophenyl;
  
  R₄is 2-carboxyethyl;
  
  R₅, R₆, and R₈are hydrogen; and
  
  R₇is chloro, or a pharmaceutically acceptable salt of any of the foregoing compounds.
- View Dependent Claims (2, 9, 20, 21, 22)
- - 2. A compound according to claim 1 wherein R₂and R_2′
    - are each attached to a stereogenic center having an R-configuration, or a pharmaceutically acceptable salt thereof.
  - 9. A composition comprising a pharmaceutically acceptable excipient and a compound or salt of claim 1, 4, or 3.
  - 20. A composition according to claim 9, wherein said composition further comprises a taxane.
  - 21. A composition according to claim 9, wherein said composition further comprises a vinca alkaloid.
  - 22. A composition according to claim 9, wherein said composition further comprises a topoisomerase I inhibitor.

3. A salt of the formula whereinR₁is benzyl;
- R₂is isopropyl;
  
  R₂′
  
  is hydrogen;
  
  R₃is p-tolyl;
  
  R₄is 3-aminopropyl;
  
  R₅is hydrogen;
  
  R₆is hydrogen;
  
  R₇is chloro; and
  
  R₈is hydrogen; and
  
  wherein said salt is a mesylate.

4. A compound of formula:
- wherein;
  
  R₁is benzyl or halobenzyl;
  
  R₂ethyl or propyl;
  
  R₂′
  
  ;
  
  R₃is substituted phenyl;
  
  R₄is —
  
  (CH₂)_mOH or —
  
  (CH₂)_pR₁₆wherein m is two or three and p is one to three;
  
  R₅is hydrogen;
  
  R₆hydrogen;
  
  R₇is halo;
  
  R₈is hydrogen; and
  
  R₁₆is chosen from amino, propylamino, and azetidinyl;
  
  or a pharmaceutically acceptable salt thereof.
- View Dependent Claims (5, 6, 7, 8, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19)
- - 5. A compound according to claim 4 wherein R₃is phenyl substituted with one or more halo, lower alkyl, lower alkoxy, nitro, carboxy, methylenedioxy, or trifluoromethyl, or a pharmaceutically acceptable salt thereof.
  - 6. A compound according to claim 4 wherein R₂and R_2′
    - are each attached to a stereogenic center having an R-configuration, or a pharmaceutically acceptable salt thereof.
  - 7. A compound according to claim 4, wherein
8. A salt according to claim 7, wherein said salt is a mesylate.
10. A compound according to claim 5 wherein R₂and R_2′
- are each attached to a stereogenic center having an R-configuration, or a pharmaceutically acceptable salt thereof.
11. A compound according to claim 7 wherein R₂and R_2′
- are each attached to a stereogenic center having an R-configuration, or a pharmaceutically acceptable salt thereof.
12. A composition comprising a pharmaceutically acceptable excipient and a compound or salt of claim 5.
13. A composition according to claim 12, wherein said composition further comprises a taxane.
14. A composition according to claim 12, wherein said composition further comprises a vinca alkaloid.
15. A composition according to claim 12, wherein said composition further comprises a topoisomerase I inhibitor.
16. A composition comprising a pharmaceutically acceptable excipient and a compound or salt of claim 7.
17. A composition according to claim 16, wherein said composition further comprises a taxane.
18. A composition according to claim 16, wherein said composition further comprises a vinca alkaloid.
19. A composition according to claim 16, wherein said composition further comprises a topoisomerase I inhibitor.

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Current Assignee
Cytokinetics, Inc.
Original Assignee
Cytokinetics, Inc.
Inventors
Feng, Bainian, Finer, Jeffrey T., Chabala, John C., Smith, Whitney W., Bergnes, Gustave
Primary Examiner(s)
Raymond, Richard L.
Assistant Examiner(s)
TRUONG, TAMTHOM NGO

Application Number

US09/699,047
Time in Patent Office

896 Days
Field of Search

514/266.3, 514/266.2, 544/284, 544/287
US Class Current

514/266.2
CPC Class Codes

A61P 1/04   for ulcers, gastritis or re...

A61P 19/02   for joint disorders, e.g. a...

A61P 29/00   Non-central analgesic, anti...

A61P 35/00   Antineoplastic agents

A61P 35/02   specific for leukemia

A61P 37/00   Drugs for immunological or ...

A61P 37/02   Immunomodulators

A61P 37/06   Immunosuppressants, e.g. dr...

A61P 43/00   Drugs for specific purposes...

A61P 9/04   Inotropic agents, i.e. stim...

A61P 9/10   for treating ischaemic or a...

C07D 239/90   with acyclic radicals attac...

C07D 239/91   with aryl or aralkyl radica...

Methods and compositions utilizing quinazolinones

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Methods and compositions utilizing quinazolinones

First Claim

1 Assignment

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0 Petitions

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Abstract

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22 Claims

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